Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice

Abstract

The body growth of animals is regulated by growth hormone and IGF-I. The classical theory of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice demonstrated complete inactivation of the IGF-I gene in the hepatocytes. Although the liver accounts for less than 5% of body mass, the concentration of IGF-I in the serum was reduced by 75%. This finding confirms that the liver is the principal source of IGF-I in the blood. However, the reduction in serum IGF-I concentration had no discernible effect on postnatal body growth. We conclude that postnatal body growth is preserved despite complete absence of IGF-I production by the hepatocytes.

Figure 1

Effects of Cre-mediated deletion of exon 4 of the IGF-I gene. Mice were induced with IFN at 24–28 days of age. Various tissues from LI-IGF-I −/− mice were analyzed 53–60 days later. (A) Southern blotting was used to determine the deletion of exon 4 of the IGF-I gene in various tissues and in an enriched hepatocyte preparation from LI-IGF-I −/− mice. The band corresponding to exon 4 of IGF-I flanked with loxP sites (Flox) and the band corresponding to deleted exon 4 (Δ) are indicated. (B) RNase-protection assay demonstrating IGF-I mRNA expression in various tissues from control and LI-IGF-I −/− mice. The IGF-I mRNA expression was normalized to the levels of 18S rRNA.

Figure 2

Serum IGF-I levels in LI-IGF −/− mice. Mice were induced with IFN at 24–28 days of age. Serum levels of IGF-I were measured 53 days later by RIA. We also investigated three different groups of control mice: mice that had been treated with IFN but lack the Mx-cre transgene (Control 1), Mx-cre transgenic mice not treated with IFN (Control 2), and mice without Mx-cre transgene and not treated with IFN (Control 3). All three control groups were homozygous for loxP sequences flanking exon 4 of the IGF-I gene (flox/flox). Because the results did not differ among the three control groups, the results were pooled (Pooled Controls). Serum IGF-I levels are expressed as percent of control and presented as mean ± SEM. The number of observations in each group is indicated within parentheses. ∗∗∗, P < 0.001.

Figure 3

Body growth in LI-IGF −/− mice. The litter sizes were similar in the LI-IGF-I mice and the control mice. Mice were induced with IFN at 24–28 days of age as described in the legend of Fig. 2. The weights of male (A) and female (B) mice at various times after IFN induction are indicated. The final weights of mice from three different experiments expressed as percent of control are indicated in C. The control groups are defined in the legend of Fig. 2. Values are expressed as mean ± SEM. The number of observations in each group is indicated within parentheses. Neither Cre expression nor IFN treatment by itself regulated any of the given parameters.